Cardiovascular disease such as atherosclerosis is caused by imbalanced lipid metabolism and represents a leading death cause in United States. Epidemiological studies showed that patients with systemic autoimmune diseases exhibit a higher incidence of atherosclerosis. Conversely, hyperlipidemia has been known to accelerate autoimmune diseases in humans and in animal models. However, there is a considerable gap in our understanding how atherosclerosis impacts the development of the autoimmunity, and vice versa. Our long-term goal is to elucidate novel cross-regulatory mechanisms governing the pathogenesis of atherosclerosis and related autoimmune diseases, which will lead to the development of novel therapeutic interventions for the treatment of these devastating diseases. The primary objective of this R01 application is to investigate the critical cross-regulation between atherosclerosis and autoimmune T cell responses with specific emphasis on Th17 responses. It is our central hypothesis that proatherogenic conditions promote autoimmune Th17 responses through T cell-intrinsic mechanisms which in turn accelerate atherosclerosis. The rationale is that identifying the cross-regulatory mechanisms will enable us to gain multi-disciplinary insights into the pathogenesis of the diseases. Guided by strong preliminary data, this hypothesis will be tested through two specific aims: 1) Determine the role of proatherogenic condition driven Th17 responses in the development of autoimmunity and atherosclerosis; 2) Determine cell-intrinsic regulation of oxidized LDL signaling in Th17 cells. Under the first aim, animal models of autoimmune lupus and atherosclerosis will be used to examine the role of proatherogenic condition-driven Th17 cells in the pathogenesis of these diseases. Under the second aim, biochemical and genetic tools will be used to dissect molecular mechanism for cell intrinsic function of oxidized LDL signaling in promoting Th17 lineage commitment. Our approach is innovative, because it employs interdisciplinary concepts and unique powerful genetic tools to examine mutual pathogenic regulation between atherosclerosis and autoimmune T cell responses by placing hyperlipidemia as an autoimmune mediator. The proposed research is highly significant, because it is anticipated to substantially advance and expand our understanding of how cardiovascular and immune systems cross-talk during the development of atherosclerosis and autoimmunity. Ultimately, such knowledge has the potential to lead to the development of novel immunologic and pharmacologic strategies for the treatment of atherosclerosis and associated autoimmune diseases.